Treatment of a depressive state with 2-[(4-piperidyl)methyl]-1,2,3,4-tetrahydroisoquinoline derivates

ABSTRACT

A compound of formula (I) ##STR1## in which R is (a) a hydrogen atom; 
     (b) a linear or branched (C 1  -C 6 ) alkyl group; an allyl group; a cycloalkylmethyl group in which the cycloalkyl moiety has from 3 to 6 carbon atoms; a phenylmethyl group unsubstituted or substituted with one to three substituents chosen from halogen atoms and trifluoromethyl, nitro, amino, dimethylamino, cyano, aminocarbonyl, linear or branched (C 1  -C 3 ) alkyl, liner or branched (C 1  -C 3 ) alkoxy and linear or branched (C 1  -C 3 ) alkylthio groups; a 2-phenylethyl group; a 3-phenylpropyl group; a 3-phenyl-2-propenyl group; a phenylcarbonylmethyl group; a naphthylmethyl group; a pyridylmethyl group; a furylmethyl group; or a thienylmethyl group; or 
     (c) a linear or branched (C 2  -C 6 ) alkanoyl group; a cycloalkylcarbonyl group in which the cycloalkyl moiety has from 3 to 6 carbon atoms; a trifluoroacetyl group; a phenylcarbonyl group unsubstituted or substituted with one to three substituents chosen from halogen atoms and trifluoromethyl, nitro, linear or branched (C 1  -C 3 ) alkyl, linear or branched (C 1  -C 3 ) alkoxy and linear or branched (C 1  -C 3 ) alkylthio groups; a 1-oxo-3-phenyl-2-propenyl group; a naphthylcarbonyl group; a pyridylcarbonyl group; a furylcarbonyl group; a thienylcarbonyl group; a (2-indolyl)carbonyl group; or a (5-indolyl)carbonyl group; or a pharmacologically acceptable acid addition salt thereof.

This application is a divisional of application Ser. No. 228,748, filedAug. 5, 1988, now U.S. Pat. No. 4,885,302, issued Dec. 5, 1989.

The present invention relates to2-[(4-piperidyl)methyl]-1,2,3,4-tetrahydroisoquinoline derivatives, totheir preparation and to pharmaceutical compositions containing them.

The present invention provides a compound of formula (I) as shown inscheme 1 on the following page, in which R is,

(a) a hydrogen atom;

(b) a linear or branched (C₁ -C₆) alkyl group, for example a methylgroup; an allyl group; a cycloalkylmethyl group in which the cycloalkylmoiety has from 3 to 6 carbon atoms, for example a cyclohexyl moiety; aphenylmethyl group unsubstituted or substituted with one to threesubstituents chosen from halogen atoms, for example chlorine or fluorineatoms, and trifluoromethyl, nitro, amino, dimethylamino, cyano,aminocarbonyl, linear or branched (C₁ -C₃) alkyl, linear or branched (C₁-C₃) alkoxy, for example methoxy or ethoxy, and linear or branched (C₁-C₃) alkylthio, for example methylthio, groups; a 2-phenylethyl group; a3-phenylpropyl group; a 3-phenyl-2-propenyl group; aphenylcarbonylmethyl group; a naphthylmethyl group; a pyridylmethylgroup; a furylmethyl group; a thienylmethyl group; or

(c) a linear or branched (C₂ -C₆) alkanoyl group, for example an acetylgroup; a cycloalkylcarbonyl group in which the cycloalkyl moiety hasfrom 3 to 6 carbon atoms, for example ##STR2## a cyclohexyl moity; atrifluoroacetyl group; a phenylcarbonyl group unsubstituted orsubstituted with one to three substituents chosen from halogen atoms,for example chlorine or fluorine atoms, and trifluoromethyl, nitro,linear or branched (C₁ -C₃) alkyl, for example methyl, linear orbranched (C₁ -C₃) alkoxy, for example methoxy or ethoxy, and linear orbranched (C₁ -C₃) alkylthio, for example methylthio, groups; a1-oxo-3-phenyl-2-propenyl group; a naphthylcarbonyl group; apyridylcarbonyl group; a furylcarbonyl group; a thienylcarbonyl group; a(2-indolyl)carbonyl group; or a (5-indolyl) carbonyl group; or apharmacologically acceptable acid addition salt thereof, for example afumarate, difumarate, hydrochloride or dihydrochloride salt.

The substituents on the phenyl rings may be in the 2,3 or 4 position ifthere is one substituent, in the 2, 3; 2, 4; 2, 5; 3, 4 or 3, 5positions if there are two substituents or in the 2,3,4; 2,3,5; 2,3,6;2,4,5 or 2, 4, 6 positions if there are three substituents.

Preferred compounds are shown in the following Table. They may bepresent in the form of the free base or as any other pharmacologicallyacceptable acid addition salt apart from the ones shown.

                  TABLE                                                           ______________________________________                                         ##STR3##                      (I)                                            No   R                     Salt    M.p. (°C.)                          ______________________________________                                        1    H                     diHCl   252-255                                    2    CH.sub.3              difum.  157-158                                    3    C.sub.6 H.sub.5CH.sub.2                                                                             diHCl   259-264                                    4    2-ClC.sub.6 H.sub.4CH.sub.2                                                                         difum.  209-211                                    5    3-ClC.sub.6 H.sub.4CH.sub.2                                                                         difum.  188-190                                    6    4-ClC.sub.6 H.sub.4CH.sub.2                                                                         difum.  205-207                                    7    2-CH.sub.3C.sub.6 H.sub.4CH.sub.2                                                                   difum.  182-183                                    8    3-CH.sub.3C.sub.6 H.sub.4CH.sub.2                                                                   difum.  185-186                                    9    4-CH.sub.3C.sub.6 H.sub.4CH.sub.2                                                                   difum.  190.5-193                                  10   2-CH.sub.3 OC.sub.6 H.sub.4CH.sub.2                                                                 difum.  177-180                                    11   3-CH.sub.3 OC.sub.6 H.sub.4CH.sub.2                                                                 difum.  173-174                                    12   4-CH.sub.3 OC.sub.6 H.sub.4CH.sub.2                                                                 difum.    204-206.5                                13   C.sub.6 H.sub.5CH.sub.2CH.sub.2                                                                     difum.  212-213                                    14   C.sub.6 H.sub.4CO     HCl     228-235                                    15   2-ClC.sub.6 H.sub.4CO fum.    95-98                                      16   3-ClC.sub.6 H.sub.4CO HCl     162-163                                    17   4-ClC.sub.6 H.sub.4CO fum.    168-170                                    18   2-CH.sub.3C.sub.6 H.sub.4CO                                                                         fum..sup.(1)                                                                          115-120                                    19   3-CH.sub.3C.sub.6 H.sub.4CO                                                                         fum.    149-151                                    20   4-CH.sub.3C.sub.6 H.sub.4CO                                                                         fum.    134-136                                    21   2-OCH.sub.3C.sub.6 H.sub.4CO                                                                        fum.    110-111                                    22   3-OCH.sub.3C.sub.6 H.sub.4CO                                                                        fum.    127-128                                    23   4-OCH.sub.3C.sub.6 H.sub.4CO                                                                        fum.    132-133                                    24   2-FC.sub.6 H.sub.4CO  fum.    131-133                                    25   3-FC.sub.6 H.sub.4CO  fum.    166-167                                    26   4-FC.sub.6 H.sub.4CO  fum.    172-174                                    27   3-CF.sub.3C.sub.6 H.sub.4CO                                                                         fum.    162 ± 164                               28   4-CF.sub.3C.sub.6 H.sub.4CO                                                                         fum.    194-195                                    29   4-NO.sub.2C.sub.6 H.sub.4CO                                                                         HCl     209-210                                    30   4-SCH.sub.3C.sub.6 H.sub.4CO                                                                        fum.    164- 166                                   31   3,5-Cl.sub.2C.sub.6 H.sub.3CO                                                                       fum.    165-166                                    32   2,3-(OCH.sub.3).sub.2C.sub.6 H.sub.3CO                                                              fum.    185-186                                    33   3,5-(OCH.sub.3).sub.2C.sub.6 H.sub.3CO                                                              fum..sup.(2)                                                                          83-86                                      34   3,5-(CH.sub.3).sub.2C.sub.6 H.sub.3CO                                                               fum.    90-95                                      35   3,5-(CF.sub.3).sub.2C.sub.6 H.sub.3CO                                                               fum..sup.(3)                                                                          105-108                                    36   C.sub.10 H.sub.7 -α-CO*                                                                       fum.    103-107                                    37   C.sub.10 H.sub.7 -β-CO*                                                                        fum.    163-165                                    38   CH.sub.3CH.sub.2CH.sub.2                                                                            difum.  186-187                                    39   CH.sub.2CHCH.sub.2    difum.  >250                                       40   C.sub.6 H.sub.5COCH.sub.2                                                                           difum.  203-205                                    41   C.sub.6 H.sub.5CH.sub.2CH.sub.2CH.sub.2                                                             difum.  153-154                                    42   2-FC.sub.6 H.sub.4CH.sub.2                                                                          difum.  189-191                                    43   3-FC.sub.6 H.sub.4CH.sub.2                                                                          difum.  184-186                                    44   4-FC.sub.6 H.sub.4CH.sub.2                                                                          difum.  183-185                                    45   3,5F.sub.2C.sub.6 H.sub.3CH.sub.2                                                                   difum.  188-190                                    46   3,5-Cl.sub.2C.sub.6 H.sub.3CH.sub.2                                                                 difum.  198-199                                    47   3,5-(CH.sub.3).sub.2C.sub.6 H.sub.3CH.sub.2                                                         difum.  203-205                                    48   3,4-(CH.sub.3 O).sub.2C.sub.6 H.sub.3CH.sub.2                                                       difum.  175-176                                    49   3,5-(CH.sub.3 O).sub.2C.sub.6 H.sub.3CH.sub.2                                                       difum.  199-201                                    50   3-NCC.sub.6 H.sub.4CH.sub.2                                                                         difum.  179-181                                    51   3-H.sub.2 NCOC.sub.6 H.sub.4CH.sub.2                                                                difum.  182-184                                    52   3-O.sub.2 NC.sub.6 H.sub.4CH.sub.2                                                                  difum.  216-217                                    53   3-H.sub.2 NC.sub.6 H.sub.4CH.sub.2                                                                  difum.  163-166                                    54   3-(CH.sub.3).sub.2 NC.sub.6 H.sub.4CH.sub.2                                                         difum.  180-182                                    55   4-CH.sub.3 SC.sub.6 H.sub.4CH.sub.2                                                                 difum.  196-198                                    56   3-CF.sub.3C.sub.6 H.sub.4CH.sub.2                                                                   difum.  193-195                                    57   3,5-(CF.sub.3).sub.2C.sub.6 H.sub.3CH.sub.2                                                         difum.  222-224                                    58   3-C.sub.2 H.sub.5 OC.sub.6 H.sub.4CH.sub.2                                                          difum.  190-192                                    59   C.sub.6 H.sub.5CHCHCH.sub.2(trans)                                                                  diHCl   197-198                                    60                                                                                  ##STR4##             fum.    115-118                                    61                                                                                  ##STR5##             fum.    180-182                                    62                                                                                  ##STR6##             fum.    179-180                                    63                                                                                  ##STR7##             fum.    169-172                                    64                                                                                  ##STR8##             fum.    174-177                                    65                                                                                  ##STR9##             fum.    151-152                                    66                                                                                  ##STR10##            fum.    171-174                                    67                                                                                  ##STR11##            fum.    203-206                                    68                                                                                  ##STR12##            fum..sup.(2)                                                                          110-125                                    69   CH.sub.3CO            fum.    139-141                                    70   nC.sub.3 H.sub.7CO    fum.    168-170                                    71   cC.sub.6 H.sub.11CO   fum.    202-204                                    72   C.sub.6 H.sub.5CH.sub.2CO                                                                           fum.    132-136                                    73   CF.sub.3CO            HCl     195-196                                    74   C.sub.6 H.sub.5CHCHCO(trans)                                                                        HCl     214-215                                    75   C.sub.10 H.sub.7 -α-CH.sub.2*                                                                 difum.  208-212                                    76   C.sub.10 H.sub.7 -β-CH.sub.2*                                                                  difum.  190-192                                    77                                                                                  ##STR13##            difum.  192-193                                    78                                                                                  ##STR14##            difum.  191-193                                    79   3,4-F.sub.2C.sub.6 H.sub.3CO                                                                        fum.    177-179                                    80   3-C.sub.2 H.sub.5 OC.sub.6 H.sub.4CO                                                                fum.    74-77                                      ______________________________________                                         Notes:                                                                        fum.: fumarate                                                                difum.: difumarate                                                            HCl: hydrochloride                                                            diHCl: dihydrochloride                                                        .sup.(1) fumarate containing one equivalent of isopropyl alcohol;             .sup.(2) fumarate hemihydrate;                                                .sup.(3) fumarate monohydrate;                                                *C.sub.10 H.sub.7 -α and C.sub.10 H.sub.7 -β denote α-       and β-naphthyl groups, respectively.                                

The compounds of formula (I) may be prepared by a process as illustratedin Scheme 1 above.

The present invention provides a process for preparing a compound offormula (I), or a pharmacologically acceptable acid addition saltthereof, in which R is a hydrogen atom, i.e., a compound of formula(IX), or a pharmacologically acceptable acid addition salt thereof,which comprises reducing a compound of formula (VI) as shown in Scheme 1with lithium aluminium hydride or a simple or complex boron hydride, forexample diborane or a borane/methyl sulphide complex, and if desired,forming a pharmacologically acceptable acid addition salt of thecompound thus obtained.

The present invention also provides a process for preparing a compund offormula (I), or a pharmacologically acceptable acid addition saltthereof, in which R is a group as defined in (b) above, which comprisesreducing a compound of formula (VII) as shown in Scheme 1 in which R isas defined above, with lithium aluminium hydride or a simple or complexboron hydride, for example diborane or a borane/methyl sulphide complex,and if desired, forming a pharmacologically acceptable acid additionsalt of the compound thus obtained.

The present invention additionally provides a process for preparing acompound of formula (I), or a pharmacologically acceptable acid additionsalt thereof, in which R is a group as defined in (c) above, i.e. acompound of formula (X) as shown in Scheme 1 in which R'CO is a group Ras defined above, or a pharmacologically acceptable acid addition saltthereof, which comprises reacting 1,2,3,4-tetrahydroisoquinoline offormula (II) as shown in Scheme 1 with a tosylate of formula (XI) asshown in Scheme 1 in which Tos is a tosylate group and R'CO is asdefined above, in the absence or presence of an inert solvent, forexample dimethylformamide or xylene, at a temperature of 20° to 150° C.,optionally in the presence of an organic or inorganic base, for examplea tertiary amine or an alkali metal carbonate or hydrogencarbonate.

The present invention further provides a process for preparing acompound of formula (I), or a pharmacologically acceptable acid additionsalt thereof, in which R is a group as defined in (c) above, i.e., acompound of formula (X) in which R'CO is a group R as defined above, ora pharmacologically acceptable acid addition salt thereof, whichcomprises reacting a compound of formula (I) in which R is hydrogen,i.e., a compound of formula (IX), with a compound of formula RY in whichR is as defined above and Y is a labile group, for example a halogenatom such as a chlorine atom, a 1-imidazolyl group, a C₁ -C₆ alkoxygroup or an acyloxy group of formula R'CO₂ wherein R'CO is the group Ras defined above, and if desired, forming a pharmacologically acceptableacid addition salt of the compound thus obtained.

For example when Y is a halogen atom the reaction may be carried out inthe presence of an organic base, for example triethylamine, in asolvent, for example dichloromethane or ethyl acetate. When Y is a1-imidazoyl group the compound of formula RY may be prepared in situfrom the corresponding acid of formula ROH and N,N'-carbonyldiimidazole.The reaction may, for example, be carried out in a solvent, such astetrahydrofuran. When Y is a C₁ -C₆ alkoxy group the compound of formula(IX) may, for example, be reacted with a trialkylaluminium, for exampletrimethylaluminium, and the complex thus formed reacted with thecompound of formula RY, for example at a temperature of from 50° to 110°C. in an inert aromatic solvent such as toluene. When Y is an acyloxygroup of formula R'CO₂ the reaction may, for example, be carried out inan inert solvent or the compound of formula RY may act as a solvent. Asuitable reaction temperature is 0° to 60° C.

The present invention also provides a process for preparing a compoundof formula (I), or a pharmacologically acceptable acid addition saltthereof, in which R is a group as defined in (b) above, which comprisesreducing a compound of formula (I) in which R is a group as defined in(c) above, i.e. a compound of formula (X) with a simple or complex boronhydride, for example diborane or a borane/methyl sulphide complex, orwith lithium aluminium hydride or aluminium hydride, in an etherealsolvent, for example diethyl ether, tetrahydrofuran or dioxane, at atemperature of from 20° to 100° C.

The present invention additionally provides a process for preparing acompound of formula (I), or a pharmacologically acceptable acid additionsalt thereof, in which R is a group as defined in (b) above, whichcomprises alkylating a compound of formula (I) in which R is a hydrogenatom, i.e. a compound of formula (IX), with a compound of formula RX inwhich R is a group as defined in (b) above and X is a labile group, forexample a halide atom, and if desired, forming a pharmacologicallyacceptable acid addition salt of the compound thus obtained.

The present invention further provides a process for preparing acompound of formula (I), or a pharmacologically acceptable acid additionsalt thereof, in which R is a hydrogen atom, i.e. a compound of formula(IX), or a pharmacologically acceptable acid addition salt thereof,which comprises hydrogenolysis of a compound of formula (I) in which Ris a phenylmethyl group in the presence of palladium, and if desired,forming a pharmacologically acceptable acid addition salt of thecompound thus obtained.

The compound of formula (VII) may, for example, be prepared byalkylating a compound of formula (VI) as shown in Scheme 1 in which R isa group as defined in (b) above with a compound of formula RX in which Ris as defined above and X is a labile group, for example a halide atomsuch as a bromine atom.

The compound of formula (VII) may also, for example, be prepared by thecatalytic hydrogenation of a compound of formula (V) as shown in Scheme1 in which R is a group as defined in (b) and X is a labile group, forexample a halide atom such as a bromine atom.

The compound of formula (VII) may additionally, for example, be preparedby reacting 1,2,3,4-tetrahydroisoquinoline of formula (II) with anisonipecotate of formula (VIII) as shown in Scheme 1 in which R is asdefined in (b), in the presence of trimethylaluminium.

The compound of formula (V) may, for example, be prepared by thealkylation of an amide of formula (IV) as shown in Scheme 1 with acompound of formula RX in which R is a group as defined in (b) and X isas defined above in relation to the compound of formula (V).

The compound of formula (VI) may be prepared, for example, byhydrogenolysis, in the presence of palladium, of a compound of formula(VII) in which R is a phenylmethyl group. It may also, for example, beprepared by catalytic hydrogenation of a compound of formula (IV), forexample under the conditions described in US-A-4,243,666.

The compound of formula (IV) may, for example, be prepared by thereaction of 1,2,3,4-tetrahydroisoquinoline with an imidazolide offormula (III) as shown in Scheme 1, prepared in situ from isonicotinicacid and N,N'-carbonyldiimidazole.

The tosylate of formula (XI) may, for example, be prepared according tothe method illustrated in Scheme 2 above.

A 4-piperidinecarboxylate of formula (XII) (in which Alk is a loweralkyl group) is reduced, for example by means of lithium aluminiumhydride, to obtain 4-piperidinemethanol of formula (XIII), which isreacted with an acid chloride of formula R'COCl, in which R'CO is agroup as defined in (b), in an inert solvent, such as a chlorinatedsolvent, at a temperature of 20° to 80° C. An ester amide of formula(XIV) is thereby obtained, which is saponified, for example by means ofsodium hydroxide or potassium hydroxide, in a lower aliphatic alcoholsolvent, preferably ethanol, to obtain an alcohol of formula (XV), whichis then reacted with tosyl chloride in a basic medium such as pyridineto form the tosylate of formula (XI).

Depending on the substituents present in the group R, it is self-evidentthat it is possible to convert, by well-known processes, some compoundsof formula (I) to other compounds of formula (I) by acting on the saidsubstituents.

Thus, for example, a compound of formula (I) in which R is aphenylmethyl group bearing an aminocarbonyl group may be obtained from acompound of formula (I) in which R is a phenylmethyl group bearing acyano group, by reacting the latter with gaseous hydrochloride acid inthe presence of formic acid.

A compound of formula (I) in which R is a phenylmethyl group bearing anamino group may be obtained from a compound of formula (I) in which R isa phenylmethyl bearing a nitro group, by reduction of the latter bymeans of diborane or the diborane/methyl sulphide complex, in anethereal solvent such as tetrahydrofuran.

A compound of formula (I) in which R is a phenylmethyl group bearing adimethylamino group may be obtained from a compound of formula (I) inwhich R is a phenylmethyl group bearing an amino group, by reductiveamination of the latter, that is to say by reaction with formaldehyde inthe presence of an acid such as sulphuric acid, in an ethereal solventsuch as tetrahydrofuran, followed by reduction of the adduct therebyobtained by means of sodium borohydride.

The Examples which follow further illustrate the present invention. Theelemental microanalyses and the IR and NMR spectra confirm thestructures of the products obtained.

The numbers given in brackets in the titles of the examples correspondto those in the table given later.

EXAMPLE 1 (Compound No. 5)2-[{1-[(3-Chlorophenyl)methyl]-4-piperidyl}methyl]-1,2,3,4-tetrahydroisoquinolinedifumarate (a) 2-[(4-Pyridinyl)carbonyl]-1,2,3,4-tetrahydroisoquinoline

50 g (406 mmol) of isonicotinic acid are dissolved under an argonatmosphere in 1000 ml of tetrahydrofuran and 25 g ofN,N'-carbonyldiimidazole are added while stirring, the mixture isstirred for half an hour, a further 25 g of N,N'carbonyldiimidazole areadded, the mixture is stirred for a further half hour and 15 g ofN,N'-carbonyldiimidazole are added. Stirring is continued for 1 h 30min, 51.39 g (385.8 mmol) of 1,2,3,4-tetrahydroisoquinoline dissolved ina few milliliters of tetrahydrofuran are introduced slowly into themixture, which has become clear, and the mixture is stirred overnight atroom temperature. The solvent is then evaporated off, the oily residuetaken up with approximately 700 ml of dichloromethane, and the solutionobtained washed twice with saturated sodium bicarbonate solution andthereafter twice with water and dried over magnesium sulphate. 87.48 gof an orange-coloured oil, which solidifies slowly in the cold, areobtained.

(b) 2-[(4-Piperidyl)carbonyl]-1,2,3,4-tetrahydroisoquinoline.

A catalytic hydrogenation of 35 g (127.3 mmol) of2-[(4-pyridyl)carbonyl]-1,2,3,4-tetrahydroisoquinoline hydrochloride in600 ml of methanol is performed in the presence of 1.2 g of platinumoxide, for 17 h, under a hydrogen pressure of 0.38 MPa. The catalyst isthen filtered off, the methanol evaporated off, the residue taken upwith ether and the insoluble material filtered off. 33.7 g ofhydrochloride are obtained, from which the base is liberated byintroducing it into a mixture of water and dichloromethane, addingpotassium carbonate portionwise to pH >10. The organic phase isseparated off and dried over sodium sulphate and the solvent evaporatedoff.

The residue is recrystallized in ether, filtered off, washed withpentane and dried. 17.2 g of base are obtained. Melting point: 200°-205°C. (decomposition).

(c)2[{1-[(3-Chlorophenyl)methyl]-4-piperidyl}carbonyl]-1,2,3,4-tetrahydroisoquinoline

5.2 g (21.3 mmol) of2-[(4-piperidyl)carbonyl]-1,2,3,4-tetrahydroisoquinoline, 4.94 g (25.5mmol) of 1-bromo-3-(chloromethyl)benzene and 4.71 g (34 mmol) ofpotassium carbonate are introduced into 100 ml of anhydrous acetone. Themixture is stirred overnight at room temperature, the acetone thenevaporated off, the residue taken up with dichloromethane and water, theorganic phase is separated off, washed and dried and the solventevaporated off. 10.5 g of product are obtained, and this is purified bychromatography on a silica column, first with dichloromethane and thenwith a 97:3 dichloromethane/methanol mixture. The purified product istaken up with pentane and the latter evaporated off. 6.13 g of pure baseare obtained. Melting point: 114°115° C.

(d)2-[{1-[(3-Chlorophenyl)methyl]-4-piperidiyl}methyl]-1,2,3,4-tetrahydroisoquinolinedifumarate

4.5 g (12.2 mmol) of2-[{1-[(3-chlorophenyl)methyl]-4-piperidyl}carbonyl]-1,2,3,4-tetrahydroisoquinolineare dissolved in 70 ml of tetrahydrofuran, 3.66 ml (36.6 mmol) of a 10Nsolution of borane/methyl sulphide complex are added, and the mixture isheated to 50° C. for 2 h and stirred for 2 days at room temperature. Themixture is then hydrolysed with 20 ml of methanol followed by 10 ml ofconcentrated hydrochloric acid, heated under reflux for 3 h and leftstanding overnight. The solvent is evaporated off and the residue takenup with ether and water, and the aqueous phase is separated off, 30%strength aqueous sodium bicarbonate is added to it to pH >10 and it isextracted with dichloromethane. The organic phase is separated off,washed with water and dried over sodium sulphate and the solventevaporated off. 4.5 g of a clear oil are obtained, and this is purifiedby chromatography on a silica column eluting with a 98:2dichloromethane/methanol mixture. 3.8 g of oil are obtained; this isdissolved in ethyl acetate and this solution is poured dropwise into asolution of fumaric acid in the minimum amount of methanol. Theprecipitated salt is filtered off, washed with ethyl acetate, acetoneand ether and dried. 3.9 g of difumarate are obtained. Melting point:188°-190° C. (decomposition).

EXAMPLE 2 (Compound No. 3) 2-[(1-Phenylmethyl-4-piperidyl)methyl]-1,2,3,4-tetrahydroisoquinolinedihydrochloride (a)2-[(1-Phenylmethyl-4-piperidyl)carbonyl]-1,2,3,4-tetrahydroisoquinoline

251 ml (594 mmol) of trimethylaluminium (at a concentration of 25% inhexane) are introduced under an argon atmosphere into 400 ml of toluene.The solution is cooled in an ice bath and 81.5 g (612 mmol) of1,2,3,4-tetrahydroisoquinoline, dissolved in 200 ml of toluene, areadded. The mixture is heated to approximately 50° C. and 95 g (384 mmol)of ethyl 1-phenylmethyl-4-piperidinecarboxylate, dissolved in 400 ml oftoluene, are added. The mixture is heated under reflux for 2 h,approximately 250 ml of solvent being removed by means of a Dean andStark apparatus. The mixture is cooled in an ice bath and hydrolysed byslowly adding 250 ml of water, and the insoluble material is filteredoff, it being rinsed with ethyl acetate. The filtrate is washed threetimes with water, the organic phase dried over sodium sulphate, thesolvent evaporated off and the residue recrystallized in cyclohexane.116.6 g of product are obtained. Melting point: 98°-100° C.

(b)2-[(1-Phenylmethyl-4-piperidyl)methyl]-1,2,3,4-tetrahydroisoquinolinedihydrochloride First variant

8 g (24 mmol) of2-[(1-phenylmethyl-4-piperidyl)carbonyl]-1,2,3,4-tetrahydroisoquinolineare introduced under an argon atmosphere into 150 ml of tetrahydrofuran,5 g (133 mmol) of sodium borohydride are added, the mixture is cooled to-10° C., 19 ml (155 mmol) of boron trifluoride/ether complex are addedand the mixture is stirred for 1 h at -10° C. The mixture is hydrolysedat 0° C. with 66 ml of 1N hydrochloric acid, neutralized withconcentrated ammonia solution and extracted with dichloromethane. Theorganic phase is separated off, washed twice with water and dried, andthe solvent evaporated off. The residue is taken up with 200 ml ofethanol, a stream of gaseous hydrochloric acid is passed through it andthe mixture is heated under reflux for 6 h. The solvent is evaporatedoff, the residue taken up with ether and water, concentrated ammoniasolution added, the organic phase separated off, washed with water anddried and the solvent evaporated off. 6.9 g of oily product areobtained, and this is dissolved in isopropyl alcohol, a stream ofgaseous hydrochloric acid is passed through it and the salt isrecrystallized in ethanol. 7.8 g of dihydrochloride are obtained.Melting point: 260°-265° C.

Second variant

60 g (179 mmol) of2-[(1-phenylmethyl-4-piperidyl)carbonyl]-1,2,3,4-tetrahydroisoquinolineare introduced portionwise under an argon atmosphere into a suspensionof 10.2 g (268 mmol) of lithium aluminium hydride in 3 l of ether heatedunder reflux. Stirring is maintained for 2 h, and the mixture is thencooled in an ice bath and hydrolysed with 24.12 ml of 1N sodiumhydroxide. The insoluble material is filtered off, the filtrateconcentrated, the residue taken up in ether and a stream of hydrogenchloride gas passed through it. The salt which precipitates is filteredoff and dried. 66.7 g of dihydrochloride are obtained. Melting point:259°-264° C.

EXAMPLE 3 (Compound No. 1)2-[(4-Piperidyl)methyl]-1,2,3,4-tetrahydroisoquinoline dihydrochloride(a) First variant

5.8 g (23.7 mmol) of2-[(4-piperidyl)carbonyl]-1,2,3,4-tetrahydroisoquinoline are added underan argon atmosphere to a solution of 0.9 g (23.7 mmol) of lithiumaluminium hydride in 150 ml of ether. The mixture is heated under refluxfor 7 h. It is cooled, and hydrolysed with 2 ml of water, the insolublematerial is filtered off, the organic phase is separated off and dried,the solvent is evaporated off, and the residue is taken up in a mixtureof isopropyl alcohol and methanol and a stream of gaseous hydrochloricacid is passed through it. 3.7 g of dihydrochloride are therebyobtained. Melting point: 252°-255° C.

(b) Second variant

A mixture of 11.2 (28.4 mmol) of2-[(1-phenylmethyl-4-piperidyl)methyl]-1,2,3,4-tetrahydroisoquinolinedihydrochloride, 1.5 g of palladinized charcoal (10% palladium) and 200ml of ethanol is subjected to a catalytic hydrogenation under a hydrogenpressure of approximately 0.41 MPa and at a temperature of 40° C. Thecatalyst is filtered off, it being rinsed with ethanol, the filtrateevaporated and the residue recrystallized in ethanol. 6.9 g ofdihydrochloride are obtained. Melting point: 252°-255° C.

EXAMPLE 4 (Compound No. 2)2-[(1-Methyl-4-piperidyl)methyl]-1,2,3,4-tetrahydroisoquinolinedifumarate. (a)1-Methyl-4-[(1,2,3,4-tetrahydro-2-isoquinolyl)carbonyl]pyridinium iodide

2 ml, equivalent to 4.26 g (30.2 mmol) of iodomethane and 6 g (25.2mmol) of 2-[(4-pyridyl)carbonyl]-1,2,3,4-tetrahydroisoquinoline areintroduced into 200 ml of ethyl acetate, and the mixture is stirred for24 h at room temperature. A yellow precipitate forms, which is filteredoff and washed with ether. 8.3 g of product are obtained, this beingused without further treatment in the following stage.

(b) 2-[(1-Methyl-4-piperidyl)carbonyl]-1,2,3,4-tetrahydroisoquinoline

4 g (10.5 mmol) of1-methyl-4-[(1,2,3,4-tetrahydro-2-isoquinolyl)carbonyl]pyridinium iodideand 0.4 g of platinum oxide are introduced into 250 ml of methanol, andthe mixture is subjected to hydrogenation for 12 h under a pressure ofapproximately 0.41 MPa. The catalyst is filtered off, the solventevaporated off and the residue neutralized, and an oil is obtained whichcrystallizes and which is used without further treatment in thefollowing stage.

(c) 2-[(1-Methyl-4-piperidyl)methyl]-1,2,3,4-tetrahydroisoquinolinedifumarate

3 g (11.6 mmol) of2-[(1-methyl-4-piperidyl)carbonyl]-1,2,3,4-tetrahydroisoquinoline aredissolved under an argon atmosphere in 100 ml of tetrahydrofuran, 0.9 gof lithium aluminium hydride is added and the mixture is heated underreflux for 4 h. Stirring is continued for 12 h at room temperature, themixture is then hydrolysed with sodium hydroxide and the organic phaseis separated off and evaporated. A yellow oil is obtained, thedifumarate of which is prepared. Melting point: 157°-158° C.

EXAMPLE 5 (Compound No. 14)2-[(1-Phenylcarbonyl-4-piperidyl)methyl]-1,2,3,4-tetrahydroisoquinolinehydrochloride (a)2-[(4-Piperidyl)carbonyl]-1,2,3,4-tetrahydroisoquinoline

115 g (0.34 mol) of2-[(1-phenylmethyl-4-piperidyl)carbonyl]-1,2,3,4-tetrahydroisoquinolineare dissolved in 1 l of acetic acid, 4 g of palladinized charcoal (10%palladium) are added and the mixture is subjected to a hydrogenation at75° C. under 0.35 MPa.

When the absorption of hydrogen is complete, the mixture is allowed toreturn to room temperature, the catalyst is filtered off and thefiltrate is concentrated under reduced pressure. The residue is taken upwith water and cooled in an ice bath, sodium hydroxide is added to it topH 10 and it is extracted with dichloromethane. The organic phase iswashed with water, and dried over sodium sulphate, the solventevaporated off and the residue crystallized in dry ether. The crystalsare filtered off, washed with pentane and dried under vacuum. 73.5 g ofproduct are obtained. Melting point: 201°-205° C. (slow decomposition).

(b) 2-[(4-Piperidyl)methyl]-1,2,3,4-tetrahydroisoquinoline hydrochloride

5.8 g (23.7 mmol) of2-[(4-piperidyl)carbonyl]-1,2,3,4-tetrahydroisoquinoline are added underan argon atmosphere to a suspension of 0.9 g (23.7 mmol) of lithiumaluminium hydride in 150 ml of ether. The mixture is heated under refluxfor 7 h. It is cooled, and hydrolysed with 2 ml of water, the insolublematerial is filtered off, the organic phase is evaporated off and dried,the solvent is evaporated off, and the residue is taken up in a mixtureof isopropyl alcohol and methanol and a stream of gaseous hydrochloricacid is passed through it. 3.7 g of dihydrochloride are therebyobtained. Melting point: 252°-255° C.

(c)2-[(1-Phenylcarbonyl-4-piperidyl)methyl]-1,2,3,4-tetrahydroisoquinolinehydrochloride

3.9 g (0.024 mol) of N,N'-carbonyldiimidazole are added in smallportions to a solution of 2.68 g (0.022 mol) of benzoic acid in 75 ml oftetrahydrofuran, placed under an argon atmosphere. The reactor isimmersed in a bath of lukewarm water and the mixture stirred for 1 h.

4.6 g (0.02 mol) of2-[(4-piperidyl)methyl]-1,2,3,4-tetrahydroisoquinoline dissolved in 75ml of tetrahydrofuran are then added, and the mixture is stirred for 6 hat room temperature and then for 9 h under reflux.

The mixture is poured into ice-cold water and extracted withdichloromethane, the organic phase separated off, washed with ammoniasolution and then with water and dried over magnesium sulphate and thesolvent evaporated off under reduced pressure.

6.2 g of oily product are obtained, and this is purified bychromatography on a silica column, eluting with a 98:2dichloromethane/methanol mixture. The base is dissolved in a littleisopropyl alcohol, a stream of gaseous hydrochloric acid is passedthrough it, and the hydrochloride which precipitates is filtered off andrecrystallized three times in ethanol. 3.0 g of hydrochloride arefinally isolated. Melting point: 228°-235° C. (decomposition).

EXAMPLE 6 (Compound No. 16)2-[{1-[(3-Chlorophenyl)carbonyl]-4-piperidyl}methyl]-1,2,3,4-tetrahydroisoquinolinehydrochloride

4.6 g (0.02 mol) of2-[(4-piperidyl)methyl]-1,2,3,4-tetrahydroisoquinoline, 2 g, equivalentto 2.8 ml (0.02 mol), of trimethylamine and 1 ml of ethyl acetate areintroduced into a round-bottomed flask. While the temperature ismaintained at approximately 20° C. using a cold bath, 3.5 g, equivalentto 2.6 ml (0.02 mol), of 3-chlorobenzoyl chloride dissolved in 50 ml ofethyl acetate are then added dropwise. The mixture is stirred for 2 h,the precipitate filtered off and washed with ethyl acetate, the filtratewashed with water and dried and the solvent evaporated off.

6.8 g of oily residue are obtained, and this is redissolved in ethylacetate, ethereal hydrochloric acid is added, the mixture is stirred for20 min, and the hydrochloride is drained, washed with ether andrecrystallized in a 50:50 isopropyl alcohol/ethyl acetate mixture. 6.5 gof white crystals are finally isolated. Melting point: 162°-163° C.

EXAMPLE 7 (Compound No. 19)2-[{1-[(3-methylphenyl)carbonyl]-4-piperidyl}methyl]-1,2,3,4-tetrahydroisoquinolinefumarate

4.6 g (0.02 mol) of2-[(4-piperidyl)methyl]-1,2,3,4-tetrahydroisoquinoline are dissolved in50 ml of dichloromethane, 2.23 g, equivalent to 3.1 ml (0.022 mol) oftriethylamine are added, and a solution of 3.4 g (0.022 mol) of3-methylbenzoyl chloride dissolved in 10 ml of dichloromethane is thenadded dropwise in the course of 20 min. The temperature of the mixturerises to 38° C. The mixture is stirred at room temperature overnight,then poured into water and extracted with dichloromethane, the organicphase is washed four times with saturated sodium chloride solution anddried over sodium sulphate and the solvent is evaporated off underreduced pressure. 7.8 g of brown oily residue are obtained, and this ispurified by chromatography on a silica column, eluting with a 90:10dichloromethane/methanol mixture, thereby yielding 6.9 g of purifiedproduct.

3.45 g of this are dissolved in 50 ml of ethanol and a solution of 1.05g of fumaric acid in 100 ml of ethanol is added thereto. The mixture isstirred for 30 min, the solvent then evaporated off under reducedpressure, the residue taken up with 250 ml of acetone and the mixtureleft to crystallize in the cold, and the crystals are filtered off anddried under reduced pressure at 90° C. 2.7 g of fumarate are finallyisolated. Melting point: 149°-151° C.

EXAMPLE 8 (Compound No. 27)2-[{1-[(3-Trifluoromethylphenyl)carbonyl]-4-piperidyl}methyl]-1,2,3,4-tetrahydroisoquinolinefumarate

A mixture of 5.2 g (0.026 mol) of2-[(4-piperidyl)methyl]-1,2,3,4-tetrahydroisoquinoline and 3.8 ml (0.027mol) of triethylamine dissolved in 20 ml of dichloromethane is addeddropwise to a solution of 4.7 g (0.0226 mol) of 3-trifluoromethylbenzoylchloride in 20 ml of dichloromethane, cooled in an ice bath.

The mixture is stirred for 20 h at room temperature and then filtered,and the filtrate is washed with water, dried and evaporated underreduced pressure. The residual oil is purified by chromatography on asilica column, 7 g of an oil are obtained and this is dissolved in 20 mlof methanol, this solution is added to 2.02 g of fumaric acid dissolvedin 20 ml of methanol, the mixture is evaporated, the residue iscrystallized in ether and the solid is then recrystallized in isopropylalcohol. 7.4 g of fumarate are finally isolated. Melting point:162°-164° C.

EXAMPLE 9 (Compound No. 41)2-[(1-Phenylcarbonylmethyl-4-piperidyl)methyl]-1,2,3,4-tetrahydroisoquinolinedifumarate

3.46 g (15 mmol) of 2-(4-piperidylmethyl)-1,2,3,4-tetrahydroisoquinolineare dissolved in 20 ml of dry dichloromethane, 4.05 g (44 mmol) of drytriethylamine are added, and a solution of 3 g (15 mmol) of2-bromo-1-phenyl-1-ethanone dissolved in 80 ml of dichloromethane arethen added dropwise to this mixture. The suspension is stirred for 3 hat room temperature and then concentrated under reduced pressure. Theevaporation residue is washed with water, the oil extracted withdichloromethane and the organic phase is separated off, dried overmagnesium sulphate and concentrated under reduced pressure. The residueis purified by chromatography on a silica column, eluting with a 95:5dichloromethane/methanol mixture. A red oil is recovered, which isdissolved in ether. An insoluble material forms which is removed byfiltration, and the filtrate is concentrated. The difumarate is preparedby dissolving 2.1 g of fumaric acid in 50 ml of methanol and adding 3.34g of base dissolved in 30 ml of ethyl acetate thereto. The saltcrystallizes, and it is washed with ethyl acetate and then with etherand dried under vacuum. Melting point: 203°-205° C.

EXAMPLE 10 (Compound No. 45)2-[{1-[(4-Fluorophenyl)methyl]-4-piperidyl}methyl]-1,2,3,4-tetrahydroisoquinolinedifumarate

3.6 g (10 mmol) of2-[{1-[(4-fluorophenyl)carbonyl]-4-piperidyl}methyl]-1,2,3,4-tetrahydroisoquinolineare dissolved under an argon atmosphere in 40 ml of tetrahydrofuran, and40 ml (40 mmol) of a molar solution of borane/tetrahydrofuran complex intetrahydrofuran are added dropwise in the course of 10 min.

The mixture is stirred for 15 min, heated under reflux for 4 h and thenleft to stand at room temperature. The complex is destroyed by adding 10ml of methanol followed by 5 ml of concentrated hydrochloric acid, andthe mixture is heated for a further 6 h under reflux.

The solvents are evaporated off under reduced pressure, the residue istaken up with water and its pH is adjusted to 10 by means ofconcentrated ammonia solution.

The mixture is extracted by means of ethyl acetate, and the organicphase washed with saturated sodium chloride solution to neutrality anddried over sodium sulphate.

The solvent is evaporated off under reduced pressure, and 4.2 g of anorange oil which partially crystallizes are obtained. It is dissolved in100 ml of ethanol, the solution is filtered and a solution of 1.85 g (16mmol) of fumaric acid in 100 ml of ethanol is added to the filtrate.

A yellow solution is obtained, which partially crystallizes. It isevaporated under reduced pressure and the residue is recrystallized in150 ml of ethanol, washed with ice-cold ether and dried under vacuum.3.4 g of difumarate are isolated. Melting point: 183°-185° C.

EXAMPLE 11 (Compound No. 49)2-[{1-[(3,4-Dimethoxyphenyl)methyl]-4-piperidyl}methyl]-1,2,3,4-tetrahydroisoquinolinedifumarate (a)1-[(3,4-Dimethoxyphenyl)methyl]-4-[(1,2,3,4-tetrahydro-2-isoquinolyl)carbonyl]pyridiniumchloride

A mixture of 4.76 g (20 mmol) of2-[(4-pyridyl)carbonyl]-1,2,3,4-tetrahydroisoquinoline, 4.5 g (24 mmol)of 3,4-dimethoxybenzyl chloride and 200 ml of ethyl acetate is heatedunder reflux for 20 h. The mixture obtained is allowed to cool, and theprecipitate is separated off by filtration and washed with ether. 6.6 gof salt are collected, this being used without further purification inthe following stage.

(b)2-[{1-[(3,4-Dimethoxyphenyl)methyl]-4-piperidyl}carbonyl]-1,2,3,4-tetrahydroisoquinoline

6.5 g of1-[(3,4-dimethoxyphenyl)methyl]-4-[(1,2,3,4-tetrahydro-2-isoquinolyl)carbonyl]pyridiniumchloride, 300 ml of ethanol and 0.7 g of platinum oxide are introducedinto a Parr bottle.

The mixture is stirred under a hydrogen pressure 0.35 MPa until theabsorption is complete, equivalent to approximately 18 h. The catalystis filtered off and washed with ethanol, and the filtrate is evaporated,neutralized with ammonia solution and extracted with dichloromethane.

The organic phase is washed with water and dried, and the solventevaporated off. 6 g of an oil are collected, this being used withoutfurther purification in the following stage.

(c)2-[{1-[(3,4-Dimethoxyphenyl)methyl]-4-piperidyl}methyl]-1,2,3,4-tetrahydroisoquinoline

A suspension of 0.6 g (15.8 mmol) of lithium aluminium hydride in 50 mlof tetrahydrofuran is stirred for 10 min, and 3 g (7.6 mmol) of2-[{1-(3,4-dimethoxyphenyl)methyl]-4-piperidyl}-carbonyl]-1,2,3,4-tetrahydroisoquinolinedissolved in 100 ml of tetrahydrofuran are then added slowly.

The mixture is heated under reflux for 5 h and allowed to cool, 1Nsodium hydroxide is added, the mixture is stirred for 20 min, theinorganic precipitate is filtered off, it being washed with ether, andthe filtrate is washed with water, dried and evaporated. 2.2 g of ayellow oil are collected, the fumarate of which is prepared by treatingit with two equivalents of fumaric acid, and the difumarate isrecrystallized in ethanol. Melting point: 175°-176° C.

EXAMPLE 12 (Compound No. 51)2-[{1-[(3-Cyanophenyl)methyl]-4-piperidyl}methyl]-1,2,3,4-tetrahydroisoquinolinedifumarate

A mixture of 6.79 g (31 mmol) of2-[(4-piperidyl)methyl]-1,2,3,4-tetrahydroisoquinoline, 7.29 g (37 mmol)of 3-(bromomethyl)benzenenitrile, 10.7 g (77 mmol) of potassiumcarbonate and 70 ml of acetone is stirred for 15 h. The mixture isfiltered, the filtrate is evaporated, water and dichloromethane areadded, and the organic phase is separated off, washed with water, driedover magnesium sulphate and evaporated. The residue is purified bychromatography on a silica column, eluting first with a 97:3dichloromethane/methanol mixture, and then a 96:4dichloromethane/methanol mixture. 6.2 g of a yellow oil are obtained.

3 g (8.6 mmol) of this are dissolved in ethyl acetate, and this solutionis poured into a solution of 1.99 g (17.2 mmol) of fumaric aciddissolved in the minimum amount of ethanol. 4.1 g of difumarate arefinally collected. Melting point: 179°-181° C.

EXAMPLE 13 (Compound No. 52)2-[{1-[(3-Aminocarbonylphenyl)methyl]-4-piperidyl}methyl]-1,2,3,4-tetrahydroisoquinolinedifumarate

A stream of gaseous hydrochloric acid is bubbled through a mixture of2.3 g (66 mmol) of2-[{1-[(3-cyanophenyl)methyl]-4-piperidyl}methyl]-1,2,3,4-tetrahydroisoquinoline(free base) and 30 ml of formic acid, the disappearance of the startingcompound being followed by thin layer chromatography.

When the reaction is complete, water, ammonia solution anddichloromethane are added, and the organic phase is separated off,washed with water, dried over magnesium sulphate, filtered andevaporated. 3.18 g of a yellow oil are obtained, and this is purified bychromatography on a silica column, eluting with dichloromethane/methanolmixtures in successive proportions of 95:5, 94:6, 93:7, 92:8, 91:9 and90:10. 1.5 g (4.1 mmol of pure base are thereby isolated, and this isdissolved in ethyl acetate and poured dropwise into 0.85 g (8.2 mmol) offumaric acid dissolved in the minimum amount of methanol. The mixtureobtained is evaporated and washed with ether and then with ethylacetate. 1.5 g of difumarate are finally isolated. Melting point:182°-184° C.

EXAMPLE 14 (Compound No. 53)2-[{1-[(3-Nitrophenyl)methyl]-4-piperidyl}methyl]-1,2,3,4-tetrahydroisoquinolinedifumarate (a)2-[{1-[(3-Nitrophenyl)methyl]-4-piperidyl}carbonyl]-1,2,3,4-tetrahydroisoquinoline

A mixture of 7 g (28.6 mmol) of2-[(4-piperidyl)carbonyl]-1,2,3,4-tetrahydroisoquinoline, 6.8 g (31.5mmol) of α-bromo-3-nitrotoluene and 6 g (43 mmol) of potassium carbonatein 140 ml of acetone is stirred for 15 h. The solvent is evaporated off,water and dichloromethane are added and the organic phase is separatedoff, neutralized, dried and evaporated. 13 g of a yellow oil areobtained, and this is purified by chromatography on a silica column,eluting with a 98:2 dichloromethane/methanol mixture. Afterrecrystallization in ether, 9.6 g of product are obtained, this beingused without further purification in the following stage.

(b)2-[{1-[(3-Nitrophenyl)methyl]-4-piperidyl}methyl]-1,2,3,4-tetrahydroisoquinolinedifumarate

A mixture of 6.6 g (17.4 mmol) of2-[{1-[(3-nitrophenyl)methyl]-4-piperidyl}carbonyl]-1,2,3,4-tetrahydroisoquinolineand 1.44 g (52 mmol) of diborane in 90 ml of tetrahydrofuran is heatedunder reflux for 5 h. The mixture is left to stand and then hydrolysedby adding 20 ml of methanol and 5 ml of concentrated hydrochloric acid.It is heated under reflux for 3 h, evaporated and taken up with water,activated charcoal is added, the mixture is stirred for 1 h at roomtemperature and filtered and the filtrate is neutralized. The organicphase is separated off and dried, the solvent evaporated off underreduced pressure and the residue purified by chromatography on a silicacolumn, eluting with a 97:3 dichloromethane/methanol mixture.

After recrystallization in pentane, 5.27 g of purified base areobtained. The difumarate is prepared by treating 2.5 g (6.84 mmol) ofbase with 1.59 g (13.7 mmol) of fumaric acid, in methanol. Meltingpoint: 216°-217° C.

EXAMPLE 15 (Compound No. 54)2-[{1-[(3-Aminophenyl)methyl]-4-piperidyl}methyl]-1,2,3,4-tetrahydroisoquinolinedifumarate

A solution of 2.7 g (7.4 mmol) of2-[{1-[(3-nitrophenyl)methyl]-4-piperidyl}methyl]-1,2,3,4-tetrahydroisoquinolinein 135 ml of acetic acid is subjected to a catalytic hydrogenation undera pressure of 0.35 MPa, in the presence of palladinized charcoal, untilthe absorption of hydrogen is complete.

The catalyst is filtered off, the filtrate concentrated under reducedpressure and the residue purified by chromatography on a silica column,eluting with a 90:10 dichloromethane/methanol mixture. Afterrecrystallization in pentane, 1.9 g of purified base are collected.

0.242 g (2.08 mmol) of fumaric acid and 0.349 g (1.04 mmol) of base aredissolved in the minimum amount of ethanol, the two solutions arecombined, the solvent is evaporated off and the residue isrecrystallized in isopropyl alcohol. 0.460 g of difumarate are finallyisolated. Melting point: 163°-166° C.

EXAMPLE 16 (Compound No. 55)2-[{1-[(3-Dimethylaminophenyl)methyl]-4-piperidyl}methyl]-1,2,3,4-tetrahydroisoquinolinedifumarate

0.805 g (26.8 mmol) of formaldehyde is dissolved in 30 ml oftetrahydrofuran, and 1.1 g (11.2 mmol) of concentrated sulphuric acidare added, followed by 1.5 g (4.47 mmol) of2-[{1-[(3-aminophenyl)methyl]-4-piperidyl}methyl]-1,2,3,4-tetrahydroisoquinoline.The mixture is stirred for 30 min at room temperature and then cooled inan ice bath, and 1.184 g (31.3 mmol) of sodium borohydride are graduallyadded thereto without the pH rising above 4.

Stirring is maintained at room temperature for 3 h, the mixture is thenevaporated, carbonated water and dichloromethane are added to theresidue, the organic phase is separated off, filtered and dried, thesolvent is evaporated off under reduced pressure and the residue ispurified by chromatography on a silica column. 0.400 g of purified baseis obtained.

0.364 g (1 mmol) of this is used for preparing with difumarate with0.221 g (1.9 mmol) of furmaric acid, according to the proceduredescribed in the preceding example. 0.250 g of difumarate is finallycollected. Melting point: 180°-182° C.

EXAMPLE 17 (Compound No. 61)2-[{1-[(2-Pyridyl)carbonyl]-4-piperidyl}methyl]-1,2,3,4-tetrahydroisoquinolinefumarate

10.05 ml (24 mmol) of trimethylaluminium (at a concentration of 25% inhexane) are added under an argon atmosphere to 20 ml of toluene. Themixture is cooled in an ice bath and 4.6 g (20 mmol) of2-[(4-piperidyl)methyl]-1,2,3,4-tetrahydroisoquinoline, diluted in 25 mlof toluene, are added.

The mixture is heated to approximately 50° C. and 3.02 g (20 mmol) ofethyl 2-pyridinecarboxylate, dissolved in 15 ml of toluene, are added,approximately 10 ml of solvents is removed by means of a Dean and Starkapparatus and the mixture is heated under reflux for 3 h.

It is then cooled in an ice bath, hydrolysed with 10 ml of water andfiltered, the solid being rinsed with ethyl acetate, the filtrate iswashed three times with water, dried over magnesium sulphate andfiltered and the solvent is evaporated off under reduced pressure.

6.7 g (20 mmol) of free base are obtained, and this is dissolved in theminimum amount of ethanol, and a solution of 2.3 g (20 mmol) of fumaricacid in 300 ml of ethanol is added. The ethanol is evaporated off andthe residue recrystallized in ethanol. 5 g of fumarate are finallyisolated. Melting point: 115°-118° C.

EXAMPLE 18 (Compound No. 68)2-[{1-[(2-Indolyl)carbonyl]-4-piperidyl}methyl]-1,2,3,4-tetrahydroisoquinolinefumarate

4.05 g (25 mmol) of N,N-carbonyldiimidazole is added in small portionsunder an argon atmosphere to a solution of 3.7 g (23 mmol) of2-indolecarboxylic acid in 37 ml of tetrahydrofuran.

The mixture is stirred for 3 h at room temperature and the solvent thenevaporated off. The residue is taken up with 46 ml of dichloromethaneand this solution is added to a solution of 4.6 g (20 mmol) of2-[(4-piperidyl)methyl]-1,2,3,4-tetrahydroisoquinoline in 40 ml ofdichloromethane.

The mixture is stirred for 12 h and then poured into water. It isextracted with dichloromethane, the organic phase washed four times withwater, dried over magnesium sulphate and filtered, the solventevaporated off under reduced pressure and the residue recrystallized intetrahydrofuran.

5 g (13.3 mmol) of free base are obtained; this is introduced into amixture of dichloromethane and methanol and a solution of 1.55 g (13.3mmol) of fumaric acid in 200 ml of ethanol is added. The mixture isheated under reflux, ethanol is added until dissolution is complete, thesolvents are then evaporated off under reduced pressure and the residueis recrystallized in ethanol. 5.5 g of fumarate are finally isolated.Melting point: 203°-206° C.

EXAMPLE 19 (Compound No. 65)2-[{1-[(3-Thienyl)carbonyl]-4-piperidyl}methyl]-1,2,3,4-tetrahydroisoquinolinefumarate (a) 3-Thiophenecarboxylic acid chloride

5.12 g (44 mmol) of 3-thiophenecarboxylic acid are added to 50 ml ofthionyl chloride, the mixture is heated to boiling for 2 h and thenevaporated, the residue is taken up with toluene and the latter isevaporated off. 5 g of residue are obtained, this being used withoutfurther treatment in the following stage.

(b)2-[{1-[(3-thienyl)carbonyl]-4-piperidyl}methyl]-1,2,3,4-tetrahydroisoquinoline

2.5 g (17 mmol) of 3-thiophenecarboxylic acid chloride dissolved in 20ml of dichloromethane are added at room temperature to a solution of 4.6g (20 mmol) of 2-[(4-piperidyl)methyl]-1,2,3,4-tetrahydroisoquinolineand 3.06 ml (22 mmol) of triethylamine in 46 ml of dichloromethane, andthe mixture is stirred for 48 h. Since the reaction is not complete, afurther 2.5 g (17 mmol) of acid chloride and 3 ml (22 mmol) oftriethylamine dissolved in 20 ml of dichloromethane are added.

The mixture is stirred for a further 1 h, poured into water andextracted with dichloromethane; the organic phase is washed twice withwater, dried over magnesium sulphate and filtered, and the solvent isevaporated off under reduced pressure.

The residue is purified by chromatography on a silica column, elutingwith a 98:2 dichloromethane/methanol mixture. 3 g (8.8 mmol) of base areobtained, this is dissolved in a mixture of dichloromethane and ethanoland a solution of 1 g (8.8 mmol) of fumaric acid in 100 ml of ethanol isadded. The solvents are evaporated off and the residue is recrystallizedin ethanol. 3.3 g of fumarate are finally isolated. Melting point:174°-177° C.

EXAMPLE 20 (Compound No. 74)2-{[-1-(Trifluoroacetyl)-4-piperidyl]methyl}-1,2,3,4-tetrahydroisoquinolinehydrochloride

2.3 g (11 mmol) of trifluoroacetic anhydride dissolved in 50 ml oftetrahydrofuran are added dropwise to a mixture of 2.3 g (10 mmol) of2-[(4-piperidyl)methyl]-1,2,3,4-tetrahydroisoquinoline, 1.4 ml (10 mmol)of triethylamine and 100 ml of tetrahydrofuran, cooled to 0° C. Thetemperature is allowed to return to 20° C. and stirring is maintainedfor 20 h.

The mixture is filtered, the filtrate washed with 10% strength aqueoussodium hydroxide solution and then with water, dried over magnesiumsulphate and filtered, and the solvent evaporated off under reducedpressure.

1.7 g of oily residue, which crystallizes, are obtained. Thehydrochloride of this is prepared by adding 0.1N hydrochloric acid inisopropyl alcohol, and is recrystallized in ethanol. Melting point:195°-196° C.

EXAMPLE 21 (Compound No. 19)2-[{1-[(3-Methylphenyl)carbonyl]-4-piperidyl}methyl]-1,2,3,4-tetrahydroisoquinolinefumarate (a) 4-Piperidinemethanol

28.5 g (0.75 mol) of lithium aluminium hydride and 1.2 l oftetrahydrofuran are introduced into a 4-l three-necked round-bottomedflask equipped with a mechanical stirring system and a condenser. 117.9g (0.75 mol) of ethyl 4-piperidinecarboxylate dissolved in 1.2 l oftetrahydrofuran are added to the suspension obtained, and the mixture isstirred for 6 h at 20° C. It is cooled to 0° C., and then hydrolysed byadding successively 22 ml of water, 22 ml of 1N sodium hydroxide and 46ml of water. The mixture is stirred for 30 min. at 20° C. and filtered,and the precipitate is washed with tetrahydrofuran and then with ether.The solvents are evaporated off under reduced pressure and 84.4 g of anoil are obtained, this being used without further treatment in thefollowing stage.

(b) [1-(3-Methylbenzoyl)-4-piperidyl]methyl 3-methylbenzoate

42.25 g (0.367 mol) of 4-piperidinemethanol and 430 ml of1,2-dichloroethane are introduced under an argon atmosphere into a 3-lthree-necked round-bottomed flask, and 82 g (0.81 mol) of triethylamineare added, followed by 125.2 g (0.81 mol) of 3-methylbenzoyl chloride.The mixture is heated under reflux for 4 h 30 min., a further 8.2 g(0.08 mol) of triethylamine and 12.5 g (0.08 mol) of 3-methylbenzoylchloride are added, and the mixture is heated for a further 3 h.

It is filtered, the salts are washed with 1,2-dichloroethane, thefiltrate is evaporated under reduced pressure, the residue is dissolvedin ethyl acetate, the solution is washed with saturated aqueous sodiumchloride solution, the solvent is evaporated off under reduced pressureand the residue is recrystallized in a 1:1 isopropyl alcohol/ethylacetate mixture. 80 g of white solid are obtained. Melting point:80°-83° C.

(c) 1-(3-Methylbenzoyl)-4-piperidinemethanol

A solution of 12.76 g (0.23 mol) of potassium hydroxide in 75 ml ofethanol and 75 ml of water is added to a solution of 80 g (0.23 mol) of[1-(3-methylbenzoyl)-4-piperidyl]methyl 3-methylbenzoate in 400 ml ofethanol. The mixture is stirred at 20° C. for 3 h, the solventevaporated off under reduced pressure and the aqueous phase extractedwith ethyl acetate. The organic phase is washed with water and then withsaturated aqueous sodium chloride solution, and dried over magnesiumsulphate. The solvent is evaporated off under reduced pressure and 53 gof alcohol are obtained, this being used without further treatment inthe following stage.

(d) [1-(3-Methylbenzoyl)-4-piperidyl]methyl 4-methylbenzenesulphonate

53.3 g (0.28 mol) of 4-methylbenzenesulphonyl chloride in 60 ml ofpyridine are added to a solution of 52 g (0.22 mol) of1-(3-methylbenzoyl)-4-piperidinemethanol in 100 ml of pyridine. Themixture is stirred at 20° C. for 4 h, and then poured into ice. Thephase is extracted with dichloromethane, and the organic phase washedwith 10N aqueous hydrochloric acid solution and dried over magnesiumsulphate. The solvents are evaporated off under reduced pressure and 70g of white solid are obtained.

Melting point: 68°-70° C.

(e)2-[{1-(3-methylphenyl)carbonyl]-4-piperidyl}methyl]-1,2,3,4-tetrahydroisoquinolinefumarate

A mixture of 2.66 g (0.02 mol) of 1,2,3,4-tetrahydroisoquinoline and7.75 g (0.02 mol) of [1-(3-methylbenzoyl)-4-piperidyl]methyl4-methylbenzenesulphonate is heated for 4 h to 150° C. The mixture isallowed to cool and is dissolved in dichloromethane, and concentratedammonia solution is added. The organic phase is separated off, washedthree times with water, dried over magnesium sulphate and evaporatedunder reduced pressure, and the residual oil is purified bychromatography on a silica column, eluting with a 98:2dichloromethane/methanol mixture. 2 g (0.0057 mol) of pure base areobtained, this is dissolved in ethanol, 0.66 g (0.0057 mol) of fumaricacid dissolved in 100 ml of ethanol is added, the ethanol is evaporatedoff and the residue is recrystallized in acetone. 2 g of fumarate arefinally isolated. Melting point: 149°-151° C.

EXAMPLE 22 (Compound No. 8) 2-[{1-[(3-Methylphenyl)methyl]-4-piperidyl}methyl]-1,2,3,4-tetrahydroisoquinoline difumarate

1.36 g of2-[{1-[(3-methylphenyl)carbonyl]-4-piperidyl}methyl]-1,2,3,4-tetrahydroisoquinolineare dissolved in 30 ml of dry ether, 0.29 g of lithium aluminium hydrideis added in a single portion and the mixture is stirred at roomtemperature for 3 h. It is cooled in an ice bath, hydrolysed with 2.4 mlof 1N sodium hydroxide and filtered, and the filtrate is evaporated. 1.2g (0.0035 mol) of base are obtained, this is dissolved in the minimumamount of ethanol, 0.82 g (0.0035 mol) of fumaric acid dissolved in 100ml of ethanol is added, and the precipitate is filtered off and dried.1.2 g of difumarate are finally obtained. Melting point: 185°-186° C.

The compounds of the invention were subjected to a series ofpharmacological tests which demonstrated their value as substanceshaving therapeutic activity.

Thus, they were subjected to a study in respect of their affinity for5-HT_(1A) type serotoninergic receptors present in the rat hippocampus.

The compounds displace the binding of a labelled specific ligand, [³H]-8-hydroxy-2-di-n-propylaminotetralin (hereinafter designated "[³H]-8-OH-DPAT" and described by Gozlan et al., Nature, (1983), 305,140-142), to the 5-HT_(1A) receptors.

The animals used are Sprague-Dawley male rats weighing 160 to 200 g.After decapitation, their brain is removed and the hippocampus excised.The tissue is ground in an Ultra-Turrax Polytron apparatus for 30 s athalf the maximum speed in 10 volumes of 50 mM Tris buffer whose pH isadjusted to 7.4 with hydrochloric acid (equivalent to 100 mg of freshtissue per ml). The homogenized tissues are washed three times at 4° C.by centrifuging them on each occasion for 10 min at 48,000×g andresuspending the pellet in cooled fresh buffer. Finally, the last pelletis suspended in the buffer to produce a concentration of 100 mg oforiginal tissue per ml of 50 mM buffer. The suspension is then left toincubate at 37° C. for 10 min.

The binding with [³ H]-8-OH-DPAT is determined by incubating 100 μl ofmembrane suspension in a final volume of 1 ml of buffer containing 10 μMpargyline and 3 μM paroxetine.

After an incubation for 15 min at 37° C. the membranes are recovered byfiltration on Whatman GF/B filters, which are washed three times with5-ml aliquot portions of ice-cold buffer. The filters are extracted inscintillation fluid and their radioactivity is measured by liquidscintigraphy. The specific binding of [³ H]-8-OH-DPAT is defined as thequantity of radioactivity retained on the filters and capable of beinginhibited by coincubation in 10 μM 5-hydroxytryptamine. At a [³H]-8-OH-DPAT concentration of 1 nM, the specific binding represents 90%of the total radioactivity recovered on the filter.

For each concentration of test compound, the percentage inhibition ofthe binding with [³ H]-8-OH-DPAT, and then the IC₅₀ concentration, theconcentration which inhibits 50% of the binding, are determined.

For the compounds of the invention, the IC₅₀ value lies between 0.001and 0.3 μM.

The central activity of the compounds of the invention was assessed bytheir effects on the "PGO (pontogeniculooccipital) spikes" induced byreserpine (PGO-R test) in cats, according to the method described by H.Depoortere, Sleep 1976, 3rd Europ. Congr. Sleep Res., Montpellier 1976,358-361 (Karger, Basel 1977).

Cumulative doses of test compounds are administered (from 0.001 to 3mg/kg intravenously) at 30-min. time intervals, 4 h after theintraperitoneal injection of a dose of 0.75 mg/kg of reserpine, tocurarized cats under artificial ventilation. The electroencephalographicand phasic (PGO-R spike) activities are obtained using cortical and deep(lateral geniculate) electrodes. For each dose of test compound, thepercentage decrease in the number of PGO spikes, and then the AD₅₀, theactive dose which decreases this number of spikes by 50%, aredetermined.

For the compounds of the invention, the intravenous ED₅₀ values liebetween 0.001 and 1 mg/kg.

The results of the tests show that the compounds of formula (I) possess,in vitro, a high affinity and a selectivity for 5-HT_(1A) typeserotoninergic receptors. In vivo, they show an agonist, partial agonistor antagonist activity with respect to these receptors.

The compounds of the invention may hence be used for the treatment ofdiseases and conditions directly or indirectly involving the 5-HT_(1A)type serotoninergic receptors, in particular for the treatment ofdepressive states, anxiety states and sleep disorders, and for theregulation of food intake, and also for the treatment of vascular,cerebrovascular or cardiovascular conditions such as migraine andhypertension.

Accordingly the present invention provides a compound of formula (I), ora pharmacologically acceptable acid addition salt thereof, for use in amethod of treatment of the human or animal body by therapy, especiallyfor use in a method of treatment of a depressive state, an anxietystate, a sleep disorder, or a vascular, cerebrovascular orcardiovascular condition or for use in the regulation of food intake.The present invention additionally provides the use of a compound offormula (I), or a pharmacologically acceptable acid addition saltthereof, in the manufacture of a medicament for the treatment of adepressive state, an anxiety state, a sleep disorder, or a vascular,cerebrovascular or cardiovascular condition or for use in the regulationof food intake.

We claim:
 1. A method of treatment of a depressive state which comprisesadministering, to a subject suffering or liable to suffer from saidstate an effective amount of the compound of formula (I) ##STR15## inwhich R is (a) a hydrogen atom;(b) a linear or branched (C₁ -C₆) alkylgroup; an allyl group; a cycloalkylmethyl group in which the cycloalkylmoiety has from 3 to 6 carbon atoms; a phenylmethyl group unsubstitutedor substituted with one to three substituents chosen from halogen atomsand trifluoromethyl, nitro, amino, dimethylamino, cyano, aminocarbonyl,linear or branched (C₁ -C₃) alkyl, linear or branched (C₁ -C₃) alkoxy anlinear or branched (C₁ -C₃) alkylthio groups; a 2-phenylethyl group; a3-phenylpropyl group; a 3-phenyl-2-propenyl group; aphenylcarbonylmethyl group; a naphthylmethyl group; a pyridylmethylgroup; a furylmethyl group; or a thienylmethyl group; or (c) a linear orbranched (C₂ -C₆) alkanoyl group; a cycloalkylcarbonyl group in whichthe cycloalkyl moiety has from 3 to 6 carbon atoms; a trifluoroacetylgroup; a phenylcarbonyl group unsubstituted or substituted with one tothree substituents chosen from halogen atoms and trifluoromethyl, nitro,linear or branched (C₁ -C₃) alkyl, linear or branched (C₁ -C₃) alkoxyand linear or branched (C₁ -C₃) alkylthio groups; a1-oxo-3-phenyl-2-propenyl group; a naphthylcarbonyl group; apyridylcarbonyl group; a furylcarbonyl group; a thienylcarbonyl group; a(2-indolyl)carbonyl group; or a (5-indolyl)carbonyl group; or apharmacologically acceptable acid addition salt thereof.